The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity

Abstract

This study identifies a GPCR, S1PR2, as a receptor for the Nogo-A-Δ20 domain of the membrane protein Nogo-A, which inhibits neuronal growth and synaptic plasticity.

Abstract

Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G ₁₃, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A ^−/− mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity.

Author Summary

Recent studies have demonstrated an important role of Nogo-A signaling in the repression of structural and synaptic plasticity in mature neuronal networks of the central nervous system. These insights extended our understanding of Nogo-A's inhibitory function far beyond its well-studied role as axonal-growth inhibitor. Repression is mediated via two different Nogo-A extracellular domains: Nogo-66 and Nogo-A-Δ20. Here, we identify the G-protein coupled receptor S1PR2 as a high-affinity receptor for Nogo-A-Δ20 and demonstrate that S1PR2 binds this domain with sites different from the recently proposed S1P binding pocket. Interfering with S1PR2 activity, either pharmacologically or genetically, prevented Nogo-A-Δ20-mediated inhibitory effects. Similar results were obtained when we blocked G ₁₃, LARG, and RhoA, components of the downstream signaling pathway. These findings revealed a strong increase in hippocampal and cortical synaptic plasticity when acutely interfering with Nogo-A/S1PR2 signaling, similar to previous results obtained by blocking Nogo-A. We thus provide a novel biological concept of multi-ligand GPCR signaling in which this sphingolipid-activated GPCR is also bound and activated by the high molecular weight membrane protein Nogo-A.